Hindawi Publishing Corporation

International Journal of Hepatology

Volume 2013, Article ID 484903, 13 pages
http://dx.doi.org/10.1155/2013/484903

Review Article
Hepatic Manifestations in Hematological Disorders

Jun Murakami1 and Yukihiro Shimizu2

1
The Third Department of Internal Medicine, Faculty of Medicine, University of Toyama,
Toyama 930-0194, Japan
2
Gastroenterology Unit, Takaoka City Hospital, Toyama 933-8550, Japan

Correspondence should be addressed to Yukihiro Shimizu; rsf14240@nifty.com

Received 23 October 2012; Revised 11 February 2013; Accepted 11 February 2013

Academic Editor: Stephen D. H. Malnick

Copyright © 2013 J. Murakami and Y. Shimizu. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Liver involvement is often observed in several hematological disorders, resulting in abnormal liver function tests, abnormalities
in liver imaging studies, or clinical symptoms presenting with hepatic manifestations. In hemolytic anemia, jaundice and
hepatosplenomegaly are often seen mimicking liver diseases. In hematologic malignancies, malignant cells often infiltrate the liver
and may demonstrate abnormal liver function test results accompanied by hepatosplenomegaly or formation of multiple nodules
in the liver and/or spleen. These cases may further evolve into fulminant hepatic failure.

1. Introduction jaundice, history of pigmented (bilirubin) gallstones, and

Hepatologists or general physicians sometimes encounter
hepatic manifestations of various hematologic disorders in
daily practice, including various abnormalities in liver func-
tion tests or imaging studies of the liver. Some hematologic
disorders also mimic liver diseases. While review articles
regarding hematologic disorders and liver diseases have been
published previously [1–3], we also review more recent topics
in this paper.
2. Red Blood Cell (RBC) Disorders
2.1. Hemolytic Anemia (HA)
2.1.1. Classification according to the RBC Destruction Site.
When the RBC membrane is severely damaged, immediate
lysis occurs within the circulation (intravascular hemolysis).
In cases of less severe damage, the cells may be destroyed
within the monocyte-macrophage system in the spleen, liver,
bone marrow, and lymph nodes (extravascular hemolysis)
[4–6].
2.1.2. Clinical Presentation. Patients with HA typically
present with the following findings: rapid onset of anemia,
splenomegaly. Mild hepatomegaly can also occur [4].
2.1.3. Liver Function Tests in HA. In hemolysis, serum lactate
dehydrogenase (LDH) levels (specifically the LDH1 and
LDH2 isoforms) increase because of lysed erythrocytes [4].
Serum aspartate transaminase (AST) levels are also mildly
elevated in hemolysis, with the LDH/AST ratio mostly over
30 [7]. Total bilirubin levels can uncommonly exceed 5 mg/dL
if hepatic function is normal, except in the case of acute
hemolysis caused by sickle cell crisis. Liver dysfunction can
also be caused by blood transfusion for anemia in sickle cell
disease (SCD) and thalassemia [1, 3].
2.1.4. Hemolysis in Liver Disease. Hemolysis can be caused by
either abnormalities in the erythrocyte membranes (intrin-
sic) or environmental (extrinsic) factors. Most intrinsic
causes are hereditary, except for paroxysmal nocturnal hemo-
globinuria (PNH) or rare conditions of acquired alpha tha-
lassemia [4].
Extrinsic HA is caused by immune or nonimmune
mechanisms. Extrinsic nonimmune HA is caused by systemic
diseases, including some infectious diseases and liver or renal
diseases. Various liver diseases may induce HA, and the two
major causes of extrinsic HA in patients with liver disease are
2 International Journal of Hepatology
destruction of RBCs in an enlarged spleen (hypersplenism)
and acquired alterations in the red cell membrane (e.g., target
cells, acanthocytes, echinocytes, and stomatocytes). Liver
diseases, especially those caused by alcohol intoxication,
induce severe hypophosphatemia [8–10], which presumably
results in low red cell adenosine triphosphate levels, leading
to red cell membrane fragility and spheroidicity. These
red cells are easily trapped in the spleen because of their
reduced deformability. When excess alcohol consumption is
the predominant cause, the condition rapidly improves when
alcohol consumption is stopped.
Zieve syndrome is a poorly understood entity charac-
terized by fatty liver/cirrhosis, severe upper abdominal and
right upper quadrant pain, jaundice, hyperlipidemia, and HA
[11–13].
2.2. Autoimmune HA (AIHA). AIHA is characterized by
increased breakdown of RBCs due to autoantibodies with or
without complement activation. Diagnosis of AIHA includes
a combination of clinical and laboratory signs of RBC
hemolysis together with detection of autoantibodies and/or
complement deposition on RBCs detected by the direct
antiglobulin test, also known as the direct Coombs test [14].
In more than half of affected patients, AIHA is associated
with an underlying disease including some type of infectious
disease, immune disorder, or lymphoproliferative disorder
(secondary AIHA), whereas other patients do not have any
evidence of underlying disorders (idiopathic or primary
AIHA) [15].
2.2.1. Liver Function Tests in AIHA. Laboratory findings
of AIHA are not different from those of other causes of
hemolysis, that is, reduction in serum haptoglobin, indirect
bilirubinemia, and elevated levels of serum LDH (I > II
predominant) and AST (mostly LDH/AST > 30). Serum
total bilirubin uncommonly exceeds 5 mg/dL, and polyclonal
hypergammaglobulinemia is often seen.
2.2.2. Liver Failure in AIHA. Immunoglobulin (Ig)G anti-
bodies (rarely IgM antibodies) generally react with antigens
on the RBC surface at body temperature and are thus
referred to as “warm agglutinins,” whereas IgM antibodies
(rarely IgG type) react with antigens on the RBC surface
below body temperature and are thus referred to as “cold
agglutinins.” Warm-reacting IgM antibodies may lead to
hepatic failure by in vivo autoagglutination [16]. A fatal case
with primary AIHA presenting as acute liver failure has been
reported [16]. The patient experienced recurrent episodes
of intravascular hemolysis. Despite corticosteroid therapy,
splenectomy, and multiple blood transfusions, the patient
eventually succumbed to liver failure.
2.3. PNH. PNH is an uncommon type of acquired hemolysis,
which occurs in middle-aged adults [17, 18]. Patients present
with dark urine (hemoglobinuria), usually the morning
samples. PNH has been proven to be an acquired clonal
genetic disease caused by somatic mutation of the X-linked
PIG-A gene in hematopoietic stem cells [19].
2.3.1. Clinical Presentation. The clinical manifestations of
PNH are primarily related to abnormalities in the hematopoi-
etic function, HA, a hypercoagulable state, bone marrow
hypoplasia or aplasia, and progression to myelodysplastic
syndrome or acute leukemia [18].
2.3.2. Diagnosis of PNH. PNH was indirectly diagnosed
formerly on the basis of the sensitivity of PNH red cells to
be lysed by complement. The sucrose lysis test is used as a
screening test, and diagnosis is confirmed by the Ham acid
hemolysis test [20–22]. However, detection of glycosylinos-
itol phospholipid-linked protein deficiency in PNH by flow
cytometric analysis has been developed for diagnosis [23].
2.3.3. PNH-Associated Liver Disease. One of the serious
complications of PNH is development of a hypercoagulable
state and formation of thrombi. Thrombosis in PNH typically
occurs in the intracranial, hepatic, or portal vessels. PNH
is one of the most common causes of de novo presentation
of portal vein thrombosis and a rare cause of Budd-Chiari
syndrome [24].
2.4. Sickle Cell Disease (SCD). SCD is an autosomal reces-
sive genetic disorder resulting from inheritance of the
hemoglobin S (Hb S) variant of the 𝛽-globin chain. The
most severe form with homozygosity for Hb S (Hb SS) is
called sickle cell anemia (SCA). Less severe forms possess
heterozygosity for Hb S and C (Hb SC) or Hb 𝛽-thalassemia
(Hb 𝛽-thal). The erythrocytes deform to a crescent shape
(sickling) prone to hemolysis, often forming clumps in the
vasculature (vaso-occlusive crisis), causing organ damages
[25].
2.4.1. Hepatic Manifestation in SCD. The liver can be affected
by the disease with vascular complications from the sickling
process. Moreover, multiple transfusions required for treat-
ment could increase the risk of viral hepatitis, iron overload,
and development of pigmented gallstones, all of which may
contribute to development of a liver disease called “sickle cell
hepatopathy” [26–28]. Acute abdominal pain and abnormal
liver function tests as well as jaundice can be caused by
acute sickle hepatic crisis, sickle cell intrahepatic cholestasis,
cholecystitis, and choledocholithiasis with common bile duct
obstruction.
2.4.2. Liver Function Tests in SCD. Liver function test abnor-
malities are common in patients with SCD. Elevation in
indirect bilirubin, LDH, and AST without other evidence of
liver disease is found in 72% of patients with SCA, which
is related to the hemolysis and/or ineffective erythropoiesis
[29]. Total bilirubin concentrations are usually <6 mg/dL
but may double (<15 mg/L) during sickle hepatic crisis [30].
Serum ALT levels may more accurately reflect hepatocyte
injury [29]. Serum alkaline phosphatase (ALP), predomi-
nantly bone derived, is commonly elevated [31].
Acute elevation in serum aminotransferase can be seen
with hepatic ischemia in vaso-occlusive crisis, whereas
chronic liver dysfunctions are found in 9%–25% of the
International Journal of Hepatology
patients [29, 32], usually caused by coexisting hepatic dis-
eases, such as chronic hepatitis B or C, common bile duct
obstruction, or alcohol consumption.
2.4.3. Hyperammonemia due to Zinc Deficiency in SCD. Low
zinc plasma levels are reported in 44% of SCD patients [33],
which may lead to development of encephalopathy due to
hyperammonemia in cirrhotic patients with SCA that can be
corrected by zinc administration [34].
2.4.4. Liver Imaging Studies in SCD. The CT findings of
patients with homozygous SCA reveal diffuse hepatomegaly.
The spleen is usually small and atrophic and may have
dense calcifications due to repeated splenic infarction. Dou-
ble heterozygotes (Hb SC and Hb S𝛽-thal) usually have
splenomegaly and may show infarcts, rupture, hemorrhage,
or abscesses of the spleen.
MRI may show decreased signal intensity in the liver and
pancreas [35] due to iron deposition in the SCD patients
receiving chronic transfusions [36–39]. Abdominal ultra-
sound can reveal gallstones or increased echogenicity of the
liver and pancreas due to iron deposition [37].
3. Coagulation Disorders
3.1. Disseminated Intravascular Coagulation (DIC). DIC is a
systemic process causing both thrombosis and hemorrhage.
The pathogenesis of DIC is primarily due to excessive pro-
duction of thrombin, leading to widespread and systemic
intravascular thrombus formation. Major initiating factors
are the release or expression of tissue factor secondary to
extensive injury to the vascular endothelium or enhanced
expression by monocytes in response to endotoxin and
various cytokines. The most common causes of DIC are
sepsis, trauma and tissue destruction, cancer, and obstetrical
complications.
3.1.1. Diagnosis of DIC. Diagnosis of DIC is suggested by the
history and symptoms, thrombocytopenia, and presence of
blood smear microangiopathic changes. The diagnosis is con-
firmed by laboratory tests that demonstrate evidence of both
increased thrombus generation (e.g., decreased fibrinogen)
as and increased fibrinolysis (e.g., elevated fibrin degradation
products or D-dimer).
3.1.2. Hepatic Manifestation in DIC. Jaundice is common
in patients with DIC and may be due to liver injury and
increased bilirubin production secondary to hemolysis. In
addition, hepatocellular injury may be produced by sepsis
and hypotension. Common manifestations of acute DIC,
in addition to bleeding, include thromboembolism and
dysfunction of the kidney, liver, lungs, and central nervous
system. In a series of 118 patients with acute DIC, hepatic dys-
function was found in 19% [38]. Severe liver disease involves
decreased synthesis of coagulation factors and inhibitors [39],
fibrinolysis, fibrinogenolysis, and elevated levels of fibrin
degradation products. Thrombocytopenia may be induced by
hypersplenism secondary to portal hypertension.
3
3.2. The Antiphospholipid Antibody Syndrome (APS). The
antiphospholipid antibody syndrome (APS) or APLA syn-
drome is characterized by the presence of one of antiphospho-
lipid antibody (aPL) in the plasma and occurrence of any clin-
ical manifestations including venous or arterial thromboses,
or pregnancy morbidity.
3.2.1. Clinical Presentation. APS occurs either as a primary or
secondary from underlying diseases such as systemic lupus
erythematosus (SLE). In a series of primary or secondary
APS, deep vein thrombosis (DVT) (32%) thrombocytope-
nia (22%), livedo reticularis (20%), stroke (13%) superficial
thrombophlebitis (9%), pulmonary embolism (9%), fetal loss
(8%), transient ischemic attack (7%) and hemolytic anemia
(7%) are often observed [40], and venous thromboses are
more common than arterial thromboses [41, 42]. Although
the most common sites where DVT occurs are the calf and
the renal veins, hepatic, axillary, subclavian, and retinal veins,
cerebral sinuses, and the vena cava may also be involved.
3.2.2. Hepatic Manifestation in APS. The liver involvement
may include hepatic or portal venous thrombosis, which
could result in Budd-Chiari syndrome, hepatic veno-
occlusive disease, hepatic infarction, portal hypertension
and cirrhosis. [40, 43].
3.3. HELLP Syndrome. HELLP syndrome is defined by
hemolysis with a microangiopathic blood smear, elevated
liver enzymes, and a low platelet count [44]. HELLP syn-
drome occurs in approximately 1 to 2 per 1000 pregnancies
and in 10 to 20 percent of women with severe preeclamp-
sia/eclampsia.
3.3.1. Clinical Presentation. The most common clinical pre-
sentation is abdominal pain [45], nausea, vomiting, and
malaise, which may resemble viral hepatitis, particularly if the
serums AST and LDH are markedly elevated [46]. Hyperten-
sion and proteinuria are present in approximately 85 percent
of the cases. Differential diagnosis includes acute fatty liver
of pregnancy (AFLP). Prolongation of the prothrombin time
activated partial thromboplastin time (aPTT), low glucose
and elevated creatinine concentrations are more common in
women with AFLP than those with HELLP.
3.3.2. Hepatic Manifestation in HELLP Syndrome. HELLP
syndrome and severe preeclampsia may be associated with
hepatic manifestations, including infarction, hemorrhage,
and rupture.
4. Cryoglobulinemia
4.1. Definition and Classification. Precipitates in serum at
temperatures below 37∘ C referred to cryoglobulin (CG). CG
consists of immunoglobulin (Ig) and complement compo-
nents [47], and the cryoglobulinemia refers to the presence of
CG in a patient’s serum. There are three types of CG according
to Brouet classification, which is based on the clonality of Ig
[48]. Type I CG (monoclonal Ig) is usually associated with a
4 International Journal of Hepatology
hematologic malignancy such as Waldenstrom’s macroglob-
ulinemia or multiple myeloma. Type II CG (polyclonal and
monoclonal Ig) is often secondary to chronic infections such
as hepatitic C or human immunodeficiency virus infection.
Type III CG (polyclonal Ig) is often secondary to systemic
rheumatic diseases.
4.2. Clinical Presentation. Clinical features of Type I CG
(monoclonal Ig) include hyperviscosity syndrome due to
hematological malignancies. While Type II and III CGs
(mixed and polyclonal Ig, resp.) are present with “Meltzer’s
triad” of palpable purpura, arthralgia, and myalgia, caused by
vasculitis in small- to medium-sized vessels [49].
Secondary lymphoproliferative disorders occur in less
than 5 to 10 percent of patients in type II CG patients 5 to
10 years after diagnosis [50–52]. The primary malignancies
include B cell non-Hodgkin lymphoma, both intermediate-
to-high grade lymphoma and low-grade lymphoma such as
immunocytoma, mucosa-associated lymphoid tumors, and
centrocytic follicular lymphoma. Among patients with hep-
atitis C-associated type II cryoglobulinemia, the incidence of
non-Hodgkin lymphoma is estimated to be 35-fold higher
than that in the general population.
4.3. Cryoglobulinemia in HCV Infection. The pathogenesis
of CG has been most studied in chronic HCV infection. B
cell hyperactivation may result from HCV infection into B
cells via the cell surface protein CD81 [53], chronic, antigen-
nonspecific stimulation by macromolecular serum complexes
containing HCV, including HCV-IgG and HCV-lipoprotein
[54, 55], or from an HCV antigen-specific mechanism [56],
resulting in expansion of specific B cell clones expressing the
WA idiotype [57] or V(H)1-69 [58]. HCV particles are often
found in the CG complexes, but CG development in hepatitis
C infection does not necessarily require HCV virion or its
components [59].
Among patients with HCV infection, the number of
circulating regulatory T cells was compared between patients
with symptomatic and asymptomatic CG [60], and the mean
levels of regulatory T cells were found to be significantly
lower in patients with symptomatic HCV-associated CG than
asymptomatic subjects.
4.4. Hepatic Manifestation of Cryoglobulinemia. Hepatic
manifestations have been reported as hepatomegaly, abnor-
mal liver function tests, or abnormal liver biopsy in up to 90
percent possibly due to chronic hepatitis itself [61].
5. Hematological Neoplasms
5.1. Classification of Neoplasms of Hematopoietic Origin.
Neoplasms derived from hematopoietic and lymphoid tissues
are classified according to their morphologic, immunophe-
notypic, genetic, and clinical features and by the type of
originating cell lineage and differentiation stage according
to the widely used and accepted World Health Organization
classification system of 2001, which was updated in 2008 [62].
Myeloid neoplasms include chronic myeloproliferative
neoplasms (MPNs), MDS, or acute leukemias with myeloid
lineages. Lymphoid neoplasms are divided into acute lym-
phoblastic leukemia/lymphoma derived from B or T lym-
phoid progenitors, or ones derived from mature T or B
lymphocytes including plasma cells. Histiocytic/dendritic cell
neoplasms are derived from antigen presenting cells or tissue
macrophages. Rare cases can be unclassifiable to myeloid or
lymphoid lineage [62].
6. Myeloid Neoplasms
Chronic MPNs, also called myeloproliferative disorders,
classically include chronic myeloid leukemia (CML), poly-
cythemia vera (PV), essential thrombocythemia, and pri-
mary idiopathic myelofibrosis.
6.1. CML. CML is an MPN characterized by dysregulated
production and uncontrolled proliferation of mature and
immature granulocytes with normal morphology. The tumor
cells are derived from a pluripotent hematopoietic stem cell
having the acquired BCR-ABL1 fusion gene, usually through
translocation between chromosomes 9 and 22, t(9; 22)(q34;
q11), referred to as the Philadelphia (Ph) chromosome. BCR-
ABL1 induces leukemogenesis through kinase dependent
and independent signaling pathways. The natural history of
CML is variable from the chronic phase to the accelerated
phase or blast crisis, but the progression process is not fully
understood [62].
6.1.1. Clinical Symptoms and Hepatic Manifestation of CML.
At presentation, 20%–50% of patients are asymptomatic.
Laboratory findings include leukocytosis with immature cells
of the granulocytic series and basophilia, mild anemia, and
thrombocytosis. Symptoms include fatigue, malaise, sweat-
ing, and weight loss. Abdominal pain and discomfort may
occur in the left upper quadrant (sometimes referred to the
left shoulder), and early satiety due to splenomegaly with
or without perisplenitis and/or splenic infarction may be
present. Variable degrees of hepatomegaly are also observed.
Tenderness over the lower sternum is sometimes present due
to expanding bone marrow, and bleeding episodes due to
platelet dysfunction are often encountered [63, 64].
In the chronic phase, approximately 50% of patients with
CML show mild to moderate hepatomegaly at presentation,
with no liver function abnormalities [65]. At the time of blas-
tic crisis, however, liver sinusoidal infiltration by immature
cells may lead to liver enlargement and elevated serum ALP
levels [66].
6.2. PV. PV is one of the chronic MPNs, and the clinical
features include an increased red cell count, splenomegaly,
thrombocytosis and/or leukocytosis, thrombotic complica-
tions, erythromelalgia, or pruritus. On physical examination,
splenomegaly, facial plethora (ruddy cyanosis), and hep-
atomegaly can be seen in 70%, 67%, and 40% of patients,
respectively [67]. Nonpalpable splenomegaly is recognized in
most patients on imaging studies [68, 69].
Gastrointestinal complaints are common in PV, with a
high incidence of epigastric distress, peptic ulcers, and gastro-
duodenal erosions on upper endoscopy [70]. These have been
International Journal of Hepatology
attributed to alterations in gastric mucosal blood flow due
to altered blood viscosity and/or increased histamine release
from tissue basophils, although one study has indicated a
high incidence of positivity for infection with Helicobacter
pylori [70]. While direct liver involvement is uncommon,
some patients may present with acute or chronic Budd-Chiari
syndrome [71].
6.3. Primary Myelofibrosis (PMF). Primary myelofibrosis
(PMF) is a chronic, malignant hematologicdisorder charac-
terized by splenomegaly, leukoerythroblastosis, bone marrow
fibrosis, and extramedullary hematopoiesis.
6.3.1. Hepatic Manifestation of PMF. At the time of PMF diag-
nosis, hepatomegaly is observed in 40%–70% of patients and
splenomegaly in at least 90% [72–74]. Hepatosplenomegaly is
caused by marked extramedullary hematopoiesis, which may
develop after splenectomy, especially in the liver [75, 76]. In
a report of 10 patients with PMF, a significant increase in the
liver size and serum concentrations of ALP, bilirubin, and/or
𝛾-GTP was seen in all of the patients who subsequently
developed acute liver failure, resulting in death 3-4 weeks
after splenectomy [76].
6.3.2. Abnormal Liver Function Tests in PMF. Patients with
PMF may have nonspecific laboratory test abnormalities,
including elevation in serum concentrations of ALP, LDH,
uric acid, leukocyte ALP, and vitamin B12 [77, 78]. Increase
in ALP may be due to liver or bone involvement of the
disease, while increase in LDH may result from ineffective
hematopoiesis.
6.4. MPNs and Portal Vein Thrombosis. MPNs can be an
uncommon cause of portal vein tyrosine kinase (V617F)
thrombosis with unexplained etiology [79–81]. JAK2 muta-
tion may be detected in such cases [82, 83].
6.5. MPNs and Budd-Chiari Syndrome. A JAK2 mutation can
be found in almost all patients with PV and approximately 50
percent of patients with essential thrombocythemia (ET) or
PMF. JAK2 (V617F) mutations have been described in 26 to
59 percent of patients with Budd-Chiari syndrome without
apparent findings of MPNs [84–87]. These findings suggest
the presence of occult MPNs in some patients with so-called
“idiopathic” Budd-Chiari syndrome.
7. Lymphoid Neoplasms
7.1. Hodgkin Lymphoma (HL). HL, formerly called Hodgkin’s
disease, is the first recognized lymphoid tumor, which usually
arises in lymph nodes and spreads in a contiguous manner
via the lymphatic system. HL is histologically characterized
by giant cells called Hodgkin/Reed-Sternberg (H/RS) cells,
most of which are transformed Epstein-Barr virus-positive B
cells present in a reactive cellular background composed of
granulocytes, plasma cells, and lymphocytes.
5
7.1.1. Hepatic Manifestations of HL. Liver infiltration of malig-
nant cells has been reported in 14% of patients with HL.
Hepatomegaly is found in 9% of patients with disease stages
I-II and in 45% of patients with stages III-IV [88]. Mild
elevation of aminotransferase and moderate elevation of ALP
can occur due to tumor infiltration or extrahepatic bile duct
obstruction [88]. Cholestasis can be caused by direct infil-
tration of lymphoma cells, extrahepatic biliary obstruction,
viral hepatitis, drug hepatotoxicity, or vanishing bile duct
syndrome [89–91]. Approximately 3%–13% of patients with
HL present with jaundice [90]. Acute liver failure can be
caused by ischemia secondary to compression of the hepatic
sinusoids by infiltrating lymphoma cells [92, 93].
7.2. Non-Hodgkin Lymphoma (NHL). NHL has been clas-
sified by cell morphology as small to large cell type and
according to the natural history of the clinical aggressiveness
of the disease as low, intermediate, or high grade.
7.2.1. Hepatic Manifestation of NHL. Lymphoma cell infil-
tration of the liver with hepatomegaly is more common in
NHL than in HL, with 16%–43% of cases showing hepatic
involvement [88]. Extrahepatic obstruction is also more
common in NHL than in HL, and hepatic infiltration is
more common in low-grade B-cell lymphomas than in high-
grade lymphomas [94]. Acute hepatic failure can occur
in NHL as seen in HL [95], which is caused by sudden
ischemia related to massive infiltration of the sinusoids or
replacement of liver parenchyma by malignant cells [95].
Although liver involvement in both HL and NHL may present
as acute hepatic failure [96–101], liver transplantation should
be avoided [102].
Acute liver failure due to lymphoma can be suspected in
cases of acute onset of hepatic enlargement and lactic acidosis
different from other causes of liver failure [2, 103].
7.2.2. Abnormal Liver Function Tests in NHL. Liver function
tests of NHL patients show mild to moderate elevation in
serum ALP [88]. Elevated level of serum LDH is also often
seen in patients with NHL, especially in highly aggressive
type such as Burkitt or lymphoblastic lymphoma, reflecting
high tumor burden, extensive infiltration of the liver, and
coincident immune-mediated HA, which are associated with
poor prognosis.
7.2.3. Imaging Studies of the Liver in NHL. Although diffuse
hepatosplenomegaly is commonly observed in patients with
indolent lymphomas, liver function is usually preserved
in NHL. On the other hand, discrete hepatic masses are
more common in the highly aggressive subtypes [104, 105].
However, not all focal liver lesions in patients with NHL are
due to lymphoma. In a report of 414 consecutive patients with
NHL, only 39% of focal liver lesions detected at disease onset
were due to NHL and 58% were benign [106], whereas 74%
of lesions detected during followup were due to NHL and
15% were due to a malignancy other than NHL (e.g., hepato-
cellular carcinoma, metastatic tumor from other secondary
6 International Journal of Hepatology
malignancy). Ascites may be present and can be chylous in
cases of lymphatic obstruction.
7.3. Primary Hepatic NHL. Primary NHL of the liver is a rare
condition, accounting for <1% of all extranodal lymphomas.
Two-thirds of cases occur in men aged approximately 50
years. Presenting symptoms include abdominal pain, fever,
hepatomegaly, and abnormal liver function tests with eleva-
tion of LDH higher than that of ALT [107, 108]. The most
common histological subtype of primary hepatic NHL is
diffuse large B-cell lymphoma, comprising 80%–90% of cases.
This disease may present with nodules in the liver or diffuse
portal infiltration and sinusoidal spread [109].
Acute liver failure from primary hepatic lymphoma
has been treated with liver transplantation and subsequent
chemotherapy [110]. Although primary hepatic lymphoma
is rare, persistent inflammatory processes associated with
HCV infection or autoimmune disease may play a role in the
lymphomagenesis of hepatic B cells [111].
7.4. Primary Hepatosplenic NHL. Primary hepatosplenic dif-
fuse large B-cell lymphoma associated with HCV has been
reported [112], and fetal acute liver failure can also occur
[113]. Although the etiological role of HCV in lymphoma is
unknown, HCV-positive lymphomas tend to arise in extra-
nodal sites, especially in the liver, spleen, or salivary glands
where HCV resides and chronic infiltration of lymphocytes
occurs.
7.5. Intravascular Diffuse Large B-Cell Lymphoma. Intravas-
cular diffuse large B-cell lymphoma or intravascular lym-
phoma is an uncommon but important condition in patients
with rapidly presenting fever, rash, or ischemic, neurologic,
or respiratory signs. With this condition, tumor cells usually
evolve exclusively within small vessels in the skin, brain,
liver, or lung. Biopsies from these organs are required for a
histologic diagnosis.
Symptoms of fever, night sweats, and weight loss are
seen in 55%–85% of B-cell lymphoma patients [114, 115].
The organs affected differ according to the area. In Western
countries, symptoms related to the central nervous system
(39%) and skin (39%) are mostly commonly experienced
[114, 116, 117], whereas those involving the bone marrow
(32%), liver (26%), and spleen (26%) are less common. In
Asia, symptoms related to involvement of the bone marrow
(75%), spleen (67%), and liver (55%) are more common
[118–121], whereas those involving the central nervous sys-
tem (27%) and skin lesions (15%) are less common [122].
Hemophagocytic syndrome has also been reported in a
Japanese series (Asian variant) [120].
Diagnosis of intravascular large cell lymphoma can be
established by random skin biopsy [123] or biopsy of organs
suspected to be involved; for example, biopsies of the liver if
unexplained abnormal liver function tests are seen, lung if
unexplained pulmonary symptoms are present, and brain if
unexplained neurological symptoms exist [124–127].
7.6. Hepatosplenic T-Cell Lymphoma
7.6.1. Clinical Presentation. Hepatosplenic T-cell lymphoma
is a rare type of aggressive NHL associated with patients
receiving antitumor necrosis factor-alpha therapy and purine
analogues to treat inflammatory bowel disease [128].
7.6.2. Hepatic Manifestation of Hepatosplenic T-Cell Lym-
phoma. Clinical features include hepatosplenomegaly, fever,
weight loss, night sweats, pancytopenia, and peripheral lym-
phocytosis. Liver function tests are elevated in approximately
50% of patients with slight elevation in AST, ALT, or ALP.
Serum LDH levels are also elevated in approximately 50% of
patients, ranging from mild to extremely high. Immunosup-
pression, especially of T cells, by antitumor necrosis factor-
alpha therapy and purine analogues may increase the risk of
this disease [129].
7.7. Hemophagocytic Syndrome (HPS)
7.7.1. Clinical Presentation. HPS is a condition presenting
with systemic inflammatory symptoms such as fever, hep-
atosplenomegaly, cytopenias, and hemophagocytosis in bone
marrow, spleen, and lymph nodes [130, 131]. HPS is caused
by hypercytokinemia, which is triggered by highly stimulated
natural killer and cytotoxic T cells. The underlying disorders
include viral infections, usually the Epstein-Barr virus in
younger patients, rheumatic disorders, immunodeficiency
syndromes, and aggressive lymphomas [132]. An aggressive
form of NK-cell lymphoma or intravascular lymphoma of
an Asian variant was reported to be complicated by HPS
[133]. HPS should be suspected if patients meet at least five
of the following eight criteria: fever, splenomegaly, cytopenia,
hypertriglyceridemia, low fibrinogen level, hemophagocyto-
sis on bone marrow biopsy, low or absent NK cell activity, or
elevated levels of ferritin or soluble IL2 receptor [130].
7.7.2. Hepatic Manifestation of HPS. HPS can cause hep-
atomegaly, jaundice with cholestasis, moderate transaminase
elevation, hyperferritinemia, decreased hepatic synthetic
function, and fulminant hepatic failure. Hepatotoxicity is
caused by hemophagocytosis in the hepatic sinusoids and
portal tracts or by focal hepatocellular necrosis [132].
8. Leukemia
8.1. Acute Leukemia
8.1.1. Clinical Presentation. Acute leukemias are neoplasms
originated from precursors of myeloid or lymphoid lineage
(rarely ambiguous lineage). Although ALL is the most com-
mon malignancy in children, the incidence is increased also
in the elderly. The incidence of AML increases with age and
AML is the most common types of adult leukemias.
International Journal of Hepatology
8.1.2. Hepatic Manifestation of Acute Leukemia. Although
hepatic involvement in acute leukemia is usually mild and
silent at the time of diagnosis [134], a postmortem study
showed liver infiltration in >95% of acute lymphoblastic
leukemia (ALL) cases and up to 75% of acute myeloid
leukemia (AML) cases [135]. In ALL, infiltration was con-
fined to the portal tracts, whereas in AML, infiltration
was observed in both portal tracts and sinusoids. Massive
leukemic cell infiltration of the liver may present as fulminant
hepatic failure [136]. In patients with acute leukemia, drug-
induced liver injury and bacterial or fungal infections may
also affect the liver.
8.1.3. AML and Hepatosplenomegaly. Palpable organomegaly
as a presentation of AML is uncommon, and significant
lymph node enlargement is rare in patients with AML.
Marked hepatosplenomegaly is also uncommon; however, if
present, the patient is likely to have ALL or evolution of AML
from a prior myeloproliferative disorder (blast crisis of CML).
8.2. ALL in Children. At presentation, several abnormali-
ties, including hepatic dysfunction, coagulation abnormali-
ties, hypercalcemia, hypocalcemia, hyperkalemia, and hyper-
phosphatemia, may be noted in children with ALL [137].
8.3. Precursor B-ALL/Lymphoblastic Lymphoma (LBL) in
Adults. Precursor B-cell ALL is associated with decrease
in normal blood cells caused by replacement of the bone
marrow with tumor cells. The clinical presentations of
patients include anemia, bleeding tendency, or susceptibility
to infections. B-symptoms such as fever, night sweats, and
weight loss are often present but may be mild. Hepatomegaly,
splenomegaly, or lymphadenopathy can be seen in up to half
of the adult patients upon presentation.
8.4. Precursor T-ALL/LBL. Precursor T-ALL/LBL originating
from thymic precursor T-cells usually occurs in males aged
approximately 20 years old. The clinical presentation includes
lymphadenopathy (50%) or an anterior bulky mediastinal
mass (50%–75%) [138]. Abdominal involvement is rare, but
it could be found primarily in the liver and spleen. More
than 80% of patients present with stage III or stage IV
disease, and almost 50% have B-symptoms and serum LDH
levels are usually elevated. Although the bone marrow is
frequently normal at presentation, approximately 60% of
patients develop bone marrow infiltration and a subsequent
leukemic phase indistinguishable from T-cell ALL [139].
8.5. Chronic Lymphoid Leukemia (CLL)
8.5.1. Clinical Presentation. Chronic lymphocytic leukemia
(CLL) is one of the chronic lymphoproliferative disorders,
characterized by a progressive accumulation of monoclonal
lymphoid cells. CLL is considered to be identical to small
lymphocytic lymphoma (SLL), which is one of the indolent
non-Hodgkin lymphomas [62, 140]. CLL is the most common
leukemia in Western countries, accounting for approximately
7
30 percent of all leukemias in the United States. Although
CLL lymphocytes resemble normal small lymphocytes in
morphology, they are activated clonal B cells at the stage
between pre-B and mature B cells. [141–143]. B-CLL lympho-
cytes are positive for B-cell-associated antigens (CD19, CD20,
CD21, and CD23) and CD5 and express extremely low levels
of surface membrane immunoglobulins (IgM or both IgM
and IgD).
8.5.2. Clinical Staging of CLL. The natural history of CLL
is heterogenous. The staging systems that are widely used
to predict patient prognosis and determine the therapeutic
strategies are the Rai system [144] and the Binet system [145].
8.5.3. Clinical Features of CLL. The most common physical
finding is lymphadenopathy, which is present in 50 to 90
percent of the patients. The other lymphoid organ frequently
enlarged in CLL is spleen, being palpable in 25 to 55 percent
of the cases.
8.5.4. Hepatic manifestation of CLL. Patients with CLL often
show mild to moderate liver enlargement at the time of initial
diagnosis in 15%–25% of cases [145, 146]. The liver is usually
only mildly enlarged, ranging from 2 to 6 cm below the
right costal margin, with a span of dullness to percussion of
approximately 10–16 cm. Upon palpation, the liver is usually
nontender and firm with a smooth surface. An enlarged liver
in patients with CLL often displays extensive lymphocytic
infiltration in the portal tracts with functional impairment of
the liver in late stages [147, 148].
8.6. Hairy Cell Leukemia (HCL)
8.6.1. Clinical Presentation. Clinical presentation of HCL
includes the following [144, 149]: (1) abdominal fullness due
to splenomegaly, which may cause spontaneous splenic rup-
ture [150], (2) systemic symptoms such as fatigue, weakness,
and weight loss without fever or night sweats, (3) bleeding
tendency secondary to severe thrombocytopenia or recurrent
infections, and (4) asymptomatic splenomegaly or cytopenias
which may be incidentally recognized, and the most common
physical sign of HCL is palpable splenomegaly (80%–90%
of cases). Massive splenomegaly extending more than 8 cm
below the left costal margin is observed in 25% of cases.
8.6.2. Hepatic Manifestation of HCL. Hepatomegaly and
lymphadenopathy are not common in HCL, presenting in
approximately 20% and 10% of patients, respectively.
8.6.3. Laboratory Findings. Most patients with HCL present
with pancytopenia (60%–80%), anemia (85%), and throm-
bocytopenia and neutropenia (80%). Leukocytosis may be
present in 10%–20% of cases. Abnormal liver function tests
and hypergammaglobulinemia are seen in 20% of cases.
Leukemia cells often infiltrate the liver, in both the portal
tracts and sinusoids, and liver enlargement has been observed
in up to 40% of patients [151].
8 International Journal of Hepatology
9. Myeloma and Related Disorder
9.1. Multiple Myeloma
9.1.1. Clinical Presentation. Multiple myeloma is one of the
neoplasms of plasma cells (i.e., terminally differentiated
B cells) and is increasingly frequent with age. It com-
monly involves bone marrow and produces a monoclonal
immunoglobulin and can cause dysfunction or damages of
various organs. Most patients with multiple myeloma present
with signs or symptoms related to the infiltration of plasma
cells into the bone or to kidney damage from excess light
chains [152].
9.1.2. Hepatic Manifestation of MM. Hepatomegaly has been
observed in 15%–40% of patients and may sometimes be
accompanied by splenomegaly [153, 154]. A Mayo clinic
series of 1027 cases from this single institution reported
relatively rare symptoms and signs of hepatomegaly (4%) and
splenomegaly (1%).
9.2. Amyloidosis
9.2.1. Clinical Presentation. Amyloidosis refers to the extra-
cellular tissue deposition of amyloid fibrils composed of low
molecular weight subunits of proteins. Two major common
causes of systemic amyloid deposition are AL and AA
amyloidosis. Immunoglobulin light chain (AL) amyloidosis
(primary amyloidosis) is composed of monoclonal light
chains, with or without plasma cell dyscrasias (multiple
myeloma and Waldenstrom’s macroglobulinemia). AA amy-
loidosis is composed of fragments of the acute phase reactant
called serum amyloid A. AA amyloidosis is typically reactive
(secondary) to chronic inflammation. The symptoms in
amyloidosis are nonspecific including fatigue and weight loss.
Organomegaly and dysfunction of affected organs, including
nephrotic syndrome, restrictive cardiomyopathy, peripheral
neuropathy, macroglossia, purpura, or a coagulopathy, are
often observed [155].
9.2.2. Hepatic Manifestation of Amyloidosis. Hepatomegaly
with or without splenomegaly is seen in 70 percent of the
patients. A cholestatic pattern with elevated liver enzymes is
seen in approximately 25 percent. Hepatic involvement can
occur in all types of amyloidosis, and histologically proven
liver involvement in systemic amyloidosis is found in 17%
to 98% of the patients [156–158]. In hepatic amyloidosis,
deposition of AA amyloid is generally seen in vessels, while
the non-AA amyloid deposits appear in a mixed pattern in
vessels, sinusoidal cells, and portal stroma [159].
Primary hepatic AL amyloidosis is a rare condition.
Hepatomegaly and elevated ALP are present in most patients,
which could be associated with poor prognosis [160].
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